This invention relates to certain 2-(4-phenyl-alkanoylpiperazin-1-yl) quinazoline compounds, pharmaceutical compositions and methods of producing .alpha..sub.1 -antagonistic activity. More particularly, this invention relates to certain 4-amino-6,7-dimethoxy-2-(4-phenyl-alkanoylpiperazin-1-yl) quinazoline compounds which exhibit a high degree of selective affinity for .alpha..sub.1 -adrenergic receptor binding sites.
The adrenergic nervous system plays a primary role in the neurogenic regulation of the cardiovascular system. The sympathetic outflow to the heart and peripheral vessels originates from the vasomotor center and travels along descending neuronal pathways interrupted by synapses, the switching units which transmit the neurological signal from higher to lower neurons and from nerve endings to cells of the effector organ. Transmission of the neurological signal across synapses is mediated chemically by a neurotransmitter which is stored in the vesicles of nerve endings. Upon arrival of the neurological signal, regulated quantities of neurotransmitter are released into the synapse where it combines with receptor sites in the cellular membrane of the next neuron or effector organ, and excites the receptor cell to propagate the neurological signal or to produce an effect in an effector organ.
The principal natural neurotransmitters specific to the adrenergic nervous system are norepinephrine and epinephrine (hereinafter "norepinephrine"), which mediate neurological transmission in some central noradrenergic neurons in the vasomotor center and elsewhere in the brain as well as peripherally in so-called postganglionic sympathetic neurons. Receptors for norepinephrine have been recognized to be proteins bound to membranes of effector cells. These receptors control the function of the effector cell, and through it the function of a whole organ or organ systems. Norepinephrine receptors are highly specific for norepinephrine and can discriminate between it and many other transmitters and molecules. However, their discrimination capability is not complete, and other related catecholamines as well as various synthetic agents have been found to bind to norepinephrine receptors.
Through observed responses of various tissues and organs to norepinephrine and related catecholamine-like compounds, it has been found that norepinephrine receptors differ substantially in different tissues where they mediate different functions. In addition, norepinephrine receptors from various tissues have been found to differ in their discriminatory abilities for other compounds. Based on the foregoing and other observations, norepinephrins receptors have been classified into at least two major groups, i.e., the .alpha.-adrenergic receptors and the .beta.-adrenergic receptors. In addition, the .alpha.-groups of receptors have been further divided into the .alpha..sub.1 -adrenergic receptor sub-group and the .alpha..sub.2 -adrenergic receptor sub-group. The .alpha..sub.1 -adrenergic receptors have been characterized as being exitatory in nature, primarily functioning to result in peripheral vascular contraction. On the other hand, the .alpha..sub.2 -adrenergic receptors have been characterized as being inhibitory in nature, primarly functioning to inhibit transmitter release through inhibition of adenylate cyclase activity.
Inasmuch as the different groups and sub-groups of adrenergic receptors mediate different functions in different bodily tissues and organs, it is highly desirable to obtain chemical compounds or entities which are highly selective for limited types of receptor sites. In this manner, isolated symptoms can be effectively treated, without affecting other unrelated tissues and organs, by selectively agonizing or antagonizing a particular sub-group of receptor sites.
One compound which has been found to selectively antagonize .alpha..sub.1 -adrenergic receptor sites is known generically as prazosin. The structure of prazosin is as follows: ##STR1## Due to its .alpha..sub.1 -adrenergic receptor selectivity and its antagonistic activity, prazosin is used as an antihypertensive agent to block .alpha..sub.1 -mediated vascular contraction. Prazosin has also been used as a model .alpha..sub.1 -antagonist in the evaluation of other compounds for .alpha..sub.1 -agonistic or -antagonistic activity and in the characterization of .alpha..sub.1 -receptor sites. The compound prazosin is disclosed in U.S. Pat. Nos. 3,511,836; 3,635,979; 3,663,706; and 4,092,315.
Although prazosin has been found to be useful as an .alpha..sub.1 -adrenergic receptor antagonist, the search continues for new compounds having improved properties. One such compound, 2-(4-[4-azido-benzoyl]-piperazin-1-yl)-4-amino-6,7-dimethoxyquinazoline having the structure: ##STR2## has been disclosed in Federation Proceedings, Vol. 41, No. 5, Abst. No. 7064, p. 1478 (Mar. 10, 1982), as exhibiting irreversible non-competitive .alpha..sub.1 -adrenergic receptor inhibition upon photolysis.